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Quantitative Model of Cell Cycle Arrest and Cellular Senescence in Primary Human Fibroblasts

Author

Listed:
  • Sascha Schäuble
  • Karolin Klement
  • Shiva Marthandan
  • Sandra Münch
  • Ines Heiland
  • Stefan Schuster
  • Peter Hemmerich
  • Stephan Diekmann

Abstract

Primary human fibroblasts in tissue culture undergo a limited number of cell divisions before entering a non-replicative “senescent” state. At early population doublings (PD), fibroblasts are proliferation-competent displaying exponential growth. During further cell passaging, an increasing number of cells become cell cycle arrested and finally senescent. This transition from proliferating to senescent cells is driven by a number of endogenous and exogenous stress factors. Here, we have developed a new quantitative model for the stepwise transition from proliferating human fibroblasts (P) via reversibly cell cycle arrested (C) to irreversibly arrested senescent cells (S). In this model, the transition from P to C and to S is driven by a stress function γ and a cellular stress response function F which describes the time-delayed cellular response to experimentally induced irradiation stress. The application of this model based on senescence marker quantification at the single-cell level allowed to discriminate between the cellular states P, C, and S and delivers the transition rates between the P, C and S states for different human fibroblast cell types. Model-derived quantification unexpectedly revealed significant differences in the stress response of different fibroblast cell lines. Evaluating marker specificity, we found that SA-β-Gal is a good quantitative marker for cellular senescence in WI-38 and BJ cells, however much less so in MRC-5 cells. Furthermore we found that WI-38 cells are more sensitive to stress than BJ and MRC-5 cells. Thus, the explicit separation of stress induction from the cellular stress response, and the differentiation between three cellular states P, C and S allows for the first time to quantitatively assess the response of primary human fibroblasts towards endogenous and exogenous stress during cellular ageing.

Suggested Citation

  • Sascha Schäuble & Karolin Klement & Shiva Marthandan & Sandra Münch & Ines Heiland & Stefan Schuster & Peter Hemmerich & Stephan Diekmann, 2012. "Quantitative Model of Cell Cycle Arrest and Cellular Senescence in Primary Human Fibroblasts," PLOS ONE, Public Library of Science, vol. 7(8), pages 1-14, August.
  • Handle: RePEc:plo:pone00:0042150
    DOI: 10.1371/journal.pone.0042150
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